ABSTRACT Early onset dystonia or DYT1 dystonia is a debilitating neurological movement disorder that first presents in children at a mean age of about 12. DYT1 dystonia is caused by a mutation in the DYT1/Tor1a gene that encodes the evolutionarily conserved torsinA protein resulting in the deletion of a single glutamic acid residue (?E302/303 or ?E). The mechanism through which the ?E mutation causes DYT1 dystonia is unclear because the basic cellular function of torsinA is unknown. Intriguing new work suggests that torsinA might function in a new cellular mechanism by which large ribonucleoprotein particles (RNPs) are exported from the nucleus via budding through the nuclear envelope. When this function of torsinA is perturbed, messenger RNAs appear to inefficiently traffic to their synaptic sites of protein synthesis, compromising neuromuscular function. The field needs to know whether this new model is correct, and if so, to identify the specific molecular mechanisms by which torsinA promotes nuclear envelope budding for RNP export. This application seeks to address these goals using the oocytes of the nematode Caenorhabditis elegans as a tractable experimental model. Mutations in the best characterized C. elegans torsinA homolog (called ooc-5 for oocyte formation abnormal five) cause defects in oocyte growth. The oocyte growth defect is the earliest developmental abnormality observed in ooc-5 mutants and therefore is likely reflective of the primary underlying biochemical and cell biological deficits observed in cells lacking torsinA/OOC-5 function. Our hypothesis is that ooc-5 mutations disrupt oogenesis by interfering in part with the nuclear export assembly, or function of oocyte growth-promoting RNPs that we have defined. Given its extensive evolutionary conservation, OOC-5/torsinA is likely to perform the same elemental protein function in C. elegans oocytes and mammalian neurons. Interestingly, prior work has shown that the mechanisms of translational regulation discovered in C. elegans oocytes are also important for the development and function mammalian neurons. This proposal capitalizes on the many experimental advantages afforded by the C. elegans germline system, including the ability to conduct high-resolution live-cell imaging and the ease of molecular genetic and biochemical manipulations. Further, our group has spent two decades pioneering the mechanisms controlling oocyte development in C. elegans. Recently, we defined proteins and mRNA components of RNPs that regulate the growth, meiotic development, and developmental potential of C. elegans oocytes. Our research team is thus ideally positioned to critically test the generality of an RNP budding role for torsinA. To assess this new role for torsinA, we will: (1) Analyze the cellular mechanisms by which OOC-5 controls the oocyte growth process; and (2) Define genetic networks that can restore function to ooc-5/torsinA mutants.